Janus kinase inhibitors, also known as JAK inhibitors or jakinibs, are a type of medication that functions by inhibiting the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signaling pathway. These inhibitors have therapeutic application in the treatment of cancer and inflammatory diseases such as rheumatoid arthritis.
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Mechanism of action
Cytokines play key roles in controlling cell growth and the immune response. Many cytokines function by binding to and activating type I and type II cytokine receptors. These receptors in turn rely on the Janus kinase (JAK) family of enzymes for signal transduction. Hence drugs that inhibit the activity of these Janus kinases block cytokine signalling.
More specifically, Janus kinases phosphorylate activated cytokine receptors. These phosphorylated receptors in turn recruit STAT transcription factors which modulate gene transcription.
The first JAK inhibitor to reach clinical trials was tofacitinib. Tofacitinib is a specific inhibitor of JAK3 (IC50 = 2 nM) thereby blocking the activity of IL-2, IL-4, IL-15 and IL-21. Hence Th2 cell differentiation is blocked and therefore tofacitinib is effective in treating allergic diseases. Tofacitinib to a lesser extent also inhibits JAK1 (IC50 = 100 nM) and JAK2 (IC50 = 20 nM) which in turn blocks IFN-? and IL-6 signalling and consequently Th1 cell differentiation.
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Molecule design
Some JAK1 inhibitors are based on a benzimidazole core.
Examples
Approved compounds
- Ruxolitinib (trade names Jakafi/Jakavi) against JAK1/JAK2 for psoriasis, myelofibrosis, and rheumatoid arthritis. Approved by the U.S. Food and Drug Administration (FDA) in November 2011 for myelofibrosis (intermediate- or high-risk) and polycythemia vera, in patients with an inadequate response or intolerance to hydroxyurea.
- Tofacitinib (trade names Xeljanz/Jakvinus, formerly known as tasocitinib and CP-690550) against JAK3 for psoriasis and rheumatoid arthritis. U.S. FDA approved it in November 2012 for rheumatoid arthritis (moderately-to-severely active) in patients who had an inadequate response or intolerance to methotrexate.
- Oclacitinib (trade name Apoquel) -- against JAK1 for the control of pruritus associated with allergic dermatitis and the control of atopic dermatitis in dogs at least 12 months of age.
In clinical trials
- Baricitinib (LY-3009104, previously INCB-28050) against JAK1/JAK2 starting phase IIb for rheumatoid arthritis.
- Filgotinib (G-146034, GLPG-0634) against JAK1 for rheumatoid arthritis and Crohn's disease.
- Gandotinib (LY-2784544) against JAK2 for myeloproliferative neoplasms.
- Lestaurtinib (CEP-701) against JAK2 for acute myeloid leukemia (AML).
- Momelotinib (GS-0387, CYT-387) against JAK1 and JAK2 for myeloproliferative disorders and relapsed/refractory metastatic pancreatic cancer.
- Pacritinib (SB1518) against JAK2 for relapsed lymphoma and advanced myeloid malignancies, also myelofibrosis, myeloproliferative neoplasms and myelodysplastic syndrome.
- Upadacitinib (ABT-494) against JAK1 starting phase III for rheumatoid arthritis.
- peficitinib (ASP015K, JNJ-54781532) mainly inhibits JAK3. Numerous clinical trials, many for rheumatoid arthritis. e.g. phase II results
Experimental drugs
- Cucurbitacin I (JSI-124).
- CHZ868 -- a type II JAK2 inhibitor for use in myeloproliferative disorders and chronic myelomonocytic leukemia (CMML).
- Tofacitinib for alopecia universalis.
- Topical tofacitinib and ruxolitinib for alopecia.
Failed agents
- Fedratinib (SAR302503). Fedratinib was a JAK2 inhibitor for the treatment of primary myelofibrosis (including in patients those previously treated with ruxolitinib), polycythemia vera and essential thrombocythemia.
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